Project Summary/Abstract Physical Sciences Inc. (PSI), in collaboration with Northeastern University (NEU), School of Pharmacy proposes to develop a novel multimodal neuro-imaging tool to support the development of new drugs and therapies for neurological disorders. The target end users are academic research laboratories and pharmaceutical companies. This imaging tool is based on two-photon excitation microscopy (TPM) to measure fluorescence signals revealing drug delivery efficacy and its effect on the neuronal function. It will be capable of both real-time tracking of the drug distribution and monitoring the neural functions of individual neurons in the animal brain in vivo. The high throughput measurement provided by this technology will facilitate multiple tasks during neurological drug development including effective compound screening, drug delivery tracking, and efficacy testing. If successful, this versatile imaging tool will significantly reduce the cycle of Central Nervous System (CNS) drug development and testing, promoting less costly and more efficient clinical translation. TPM is a widely used imaging technology in neuroscience research. However, existing research- orientated TPM systems are extremely expensive and complicated, and thus have very limited use in the pharmaceutical industry and biotechnology companies. The proposed project aims to develop an affordable and easy-to-use TPM instrument to promote its translation of this enabling technology to pharmaceutical applications. This aim will be achieved by leveraging innovative approaches, including: 1) a compact and low-cost fiber-delivered coherent supercontinuum (SC) source to provide multiple wavelengths selectively used for optimal excitation of different fluorophores, and 2) a novel design for a compact high-performance TPM neurofunctional imaging microscope that will easily interface with animal brain. This unique TPM instrument will have an adjustable optical head, which will substantially facilitate many in vivo brain investigations. The low cost and high portability will promote the wide-spread adoption of the technology within the pharmaceutical industry. During the Phase I program PSI will focus on demonstrating the feasibility of proposed approaches. A prototype instrument will be fabricated at PSI, and then delivered to NEU for animal testing. Proof of concept experiments will be performed to demonstrate the effectiveness of the prototype for real-time tracking of drug delivery and assessing the neuronal functions before and after the application of neurological drugs. A subsequent Phase II program would further refine the technology and test it during large scale animal studies, preparing it for commercialization. The achievement of this goal will be supported by the expertise and proven track record of the PSI investigators in developing advanced biomedical devices, as well as by the pharmaceutical science and drug development expertise of the research group at Northeastern University School of Pharmacy.